Cytokine Storm and an Anti-CD28 Monoclonal Antibody
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The events of the phase 1 trial of TGN1412, as detailed by Suntharalingam et al. (Sept. 7 issue),1 are a sobering reminder of the risks that research volunteers take when they participate in trials, but the article did not contain any comments on the subjects' mental state as they emerged from this near-death experience. The volunteers did not just suffer insults to kidney and pulmonary function; they were afflicted emotionally and perhaps intellectually as well. When an experimental drug has such serious adverse effects, it is worth reporting the psychological effects, which inform the ethical impact of testing experimental regimens and advance our understanding of the management of psychological harm. Without mention of the afflicted subjects' ability to return to their normal lives and their jobs or of psychological counseling offered to them, I view the article by Suntharalingam et al. as incomplete.
Keri Gardner, M.D., M.P.H.
UCLA School of Medicine
Los Angeles, CA 90024
kerik@ucla.edu
References
Suntharalingam G, Perry MR, Ward S, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 2006;355:1018-1028.
To the Editor: We believe that the cytokine-release syndrome strongly resembles the toxic shock syndrome, which is induced by a staphylococcal superantigen that activates T cells, through their antigen receptor, to induce massive cytokine release.1 However, mice with deletion of the CD28 gene are protected from superantigen-induced, toxic shock syndrome–like disease.2 In addition, peptides that block binding to CD28 also block superantigen-dependent cytokine secretion by T cells.3 Together, these observations indicate that T cells activated by superantigen binding to both CD28 and the antigen receptor mediate the toxic shock syndrome.
CD28-deficient mice are protected from lethal superantigen challenge through the selective abrogation of the release of tumor necrosis factor (TNF).2 Because TNF is also strongly induced by anti-CD28 antibodies and TNF infusion can induce toxic shock syndrome–like disease,4 short-term use of anti-TNF agents may benefit patients with the toxic shock syndrome and related syndromes involving "cytokine storm."
David B. Corry, M.D.
Dorothy E. Lewis, Ph.D.
Baylor College of Medicine
Houston, TX 77030
dcorry@bcm.tmc.edu
References
McCormick JK, Yarwood JM, Schlievert PM. Toxic shock syndrome and bacterial superantigens: an update. Annu Rev Microbiol 2001;55:77-104.
Saha B, Harlan DM, Lee KP, June CH, Abe R. Protection against lethal toxic shock by targeted disruption of the CD28 gene. J Exp Med 1996;183:2675-2680.
Arad G, Levy R, Hillman D, Kaempfer R. Superantigen antagonist protects against lethal shock and defines a new domain for T-cell activation. Nat Med 2000;6:414-421.
Remick DG, Kunkel RG, Larrick JW, Kunkel SL. Acute in vivo effects of human recombinant tumor necrosis factor. Lab Invest 1987;56:583-590.
To the Editor: CD28 expression by human neutrophils has been documented, and its activation alone results in the secretion of interferon-.1 We now find that a subgroup of human neutrophils expresses the T-cell receptor (Figure 1). We have also shown that costimulation of the T-cell receptor and CD28 triggers the release of interleukin-8 in these cells.2 Therefore, neutrophils may represent a quantitatively important target of TGN1412 and may link the pathogenesis of the cytokine-release syndrome to the innate immune system.
Figure 1. Human Neutrophils Expressing the T-Cell Receptor.
Expression of the T-cell receptors and (indicated in red) is shown in a normal human peripheral-blood neutrophil (Panel A) and in a lymphocyte from the same person, used as a control cell (Panel B). Cells were double-stained with a monoclonal antibody against the T-cell receptors and (red) and the neutrophil marker CD15 (green); the nuclei were counterstained with 4',6-diamidine-2-phenylidole dihydrochloride (blue). Panel C shows the presence of the T-cell receptors and on the surface of a peripheral-blood neutrophil on immunogold electron microscopy. Arrows indicate T-cell receptor heterodimers (pairs).
Kerstin Puellmann, M.D.
Alexander W. Beham, M.D.
University of Regensburg
93053 Regensburg, Germany
kerstin.puellmann@web.de
Wolfgang E. Kaminski, M.D.
University of Heidelberg
68167 Mannheim, Germany
References
Venuprasad K, Banerjee PP, Chattopadhyay S, et al. Human neutrophil-expressed CD28 interacts with macrophage B7 to induce phosphatidylinositol 3-kinase-dependent IFN-gamma secretion and restriction of Leishmania growth. J Immunol 2002;169:920-928.
Puellmann K, Kaminski WE, Vogel M, et al. A variable immunoreceptor in a subpopulation of human neutrophils. Proc Natl Acad Sci U S A 2006;103:14441-14446.
To the Editor: The TGN1412-exposed patients described by Suntharalingam et al. had many of the clinical and laboratory features of the macrophage activation syndrome, also known as secondary hemophagocytic lymphohistiocytosis, a severe and sometimes fatal condition.1,2 Unfortunately, important diagnostic criteria for the macrophage activation syndrome,3,4 such as increased ferritin and soluble CD25 levels, enhanced activity of natural killer cells, and specific histologic characteristics of bone marrow, were not reported in these patients. Also, hepatosplenomegaly and lymphadenopathy, which are classic features of the macrophage activation syndrome, were absent in the volunteers exposed to TGN1412, perhaps because of the very acute nature of the reaction. If characterized further, TGN1412 may provide insight into the mechanisms that lead to the macrophage activation syndrome in other clinical settings, such as juvenile idiopathic arthritis or sepsis. This understanding may also help in the handling of future situations similar to the one described by Suntharalingam et al., in which evidence from clinical trials, including those involving patients with the macrophage activation syndrome, could help guide the care of the affected patients.3
Facundo Garcia-Bournissen, M.D.
Mariana Boragina, M.D.
Shinya Ito, M.D.
Hospital for Sick Children
Toronto, ON M5G 1X8, Canada
facundo.garciabournissen@sickkids.ca
References
Emmenegger U, Schaer DJ, Larroche C, Neftel KA. Haemophagocytic syndromes in adults: current concepts and challenges ahead. Swiss Med Wkly 2005;135:299-314.
Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child 2001;85:421-426.
Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer (in press).
Ravelli A, Magni-Manzoni S, Pistorio A, et al. Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr 2005;146:598-604.
To the Editor: Suntharalingam et al. report severe adverse events in the phase 1 study of TGN1412. Monoclonal antibodies, which cannot be metabolized in the liver and cannot be eliminated from the kidney, usually have long half-lives.1 Double filtration plasmapheresis, which selectively removes high-molecular-weight substances, including immunoglobulins and immune complexes, has been proven to be effective for the clearance of circulating monoclonal antibodies,2 and some studies have shown the usefulness of continuous hemofiltration or continuous hemodiafiltration for ameliorating cytokine storm.3,4 We would like the authors to comment on whether these therapeutic measures might be beneficial for the treatment of severe adverse events associated with monoclonal antibodies.
Morihito Takita, M.D.
Tomoko Matsumura, M.D.
Masahiro Kami, M.D.
University of Tokyo
Tokyo 108-8639, Japan
References
Expert scientific group on phase 1 clinical trials: interim report. London: Secretary of State for Health, July 2006. (Accessed November 22, 2006, at http://www.dh.gov.uk/assetRoot/04/13/75/69/04137569.pdf.)
Yeh JH, Chen WH, Chiu HC, Bai CH. Clearance studies during subsequent sessions of double filtration plasmapheresis. Artif Organs 2006;30:111-114.
Heering P, Morgera S, Schmitz FJ, et al. Cytokine removal and cardiovascular hemodynamics in septic patients with continuous venovenous hemofiltration. Intensive Care Med 1997;23:288-296.
Iglesias J, Marik PE, Levine JS. Elevated serum levels of the type I and type II receptors for tumor necrosis factor-alpha as predictive factors for ARF in patients with septic shock. Am J Kidney Dis 2003;41:62-75.
The authors reply: The psychological effect of serious adverse events on healthy subjects involved in clinical trials is important; critical illness has its own known neuropsychological consequences.1,2 Our institution does provide follow-up after discharge of patients who stay in the intensive care unit for more than 3 days. However, our article was limited to the physiological and immunologic events that occurred within 30 days after exposure; the omission cited by Gardner does not make the report incomplete.
Corry and Lewis suggest that the cytokine storm induced by TGN1412 is similar to that resulting in the toxic shock syndrome, on the basis of the activation of CD28 on T cells. Although T cells were the intended targets of TGN1412, it is still unclear whether T-cell activation induced the cytokine storm. The trigger may have been on another type of cell expressing CD28, as suggested by Puellmann et al., or may have involved ligation of Fc receptors. Hence the macrophage activation syndrome was also considered. Since the neutrophil count was preserved and, as noted by Garcia-Bournissen et al., there was neither hepatosplenomegaly nor lymphadenopathy, we thought that the macrophage activation syndrome as a separate entity should be ruled out. Our article was a clinical report of the unintended consequences of a phase 1 trial and subsequent emergency care. Laboratory investigations were limited to those that were of direct clinical benefit.
Anti-TNF therapy was considered. When transfer to our care took place 12 to 16 hours after TGN1412 infusion, we decided that the TNF peak was likely to have passed and that downstream events had already been triggered. As cytokine data became available, showing persistently high TNF levels, this decision was reviewed. In our minds, in the setting of severe lymphopenia and monocytopenia of unknown duration, treatment with high-dose corticosteroids and anti–interleukin-2 receptor antagonist antibody, and the increased risk of secondary infections in the patients, the risk of anti-TNF therapy still outweighed its potential benefit. We would be yet more cautious with a cause associated with infection, such as the toxic shock syndrome.
We agree with Takita et al. Plasmapheresis was considered, but the known pharmacokinetics of a low IgG4 antibody level suggested that the drug would be tissue-bound. We also agree that there may be a role for continuous venovenous hemodiafiltration in blunting the cytokine storm associated with a severe systemic inflammatory response. Furthermore, high dialysate rates3 and high-cutoff filters4 have previously been suggested for use in treating sepsis. Our patients received continuous venovenous hemodiafiltration at an initial dialysate rate of 1 liter per hour, which was subsequently raised to 4 liters per hour, using standard membranes. In our opinion, aggressive multiorgan support and early institution of high-volume diafiltration and treatment with high-dose corticosteroids, combined with the physiological resilience of these six young, healthy research volunteers, were key to their survival.
Andrew Castello-Cortes, F.R.C.A.
Ganesh Suntharalingam, F.R.C.A.
Northwick Park and St. Mark's Hospital
London HA1 3UJ, United Kingdom
ganesh.suntharalingam@nwlh.nhs.uk
Nicki Panoskaltsis, M.D., Ph.D.
Imperial College London
London HA1 3UJ, United Kingdom
References
Sukantarat KT, Burgess PW, Williamson RC, Brett SJ. Prolonged cognitive dysfunction in survivors of critical illness. Anaesthesia 2005;60:847-853.
Jackson JC, Hart RP, Gordon SM, et al. Six-month neuropsychological outcome of medical intensive care unit patients. Crit Care Med 2003;31:1226-1234.
Cole L, Bellomo R, Journois D, Davenport P, Baldwin I, Tipping P. High-volume haemofiltration in human septic shock. Intensive Care Med 2001;27:978-986.
Morgera S, Klonower D, Rocktaschel J, et al. TNF-alpha elimination with high cut-off haemofilters: a feasible clinical modality for septic patients? Nephrol Dial Transplant 2003;18:1361-1369.
Keri Gardner, M.D., M.P.H.
UCLA School of Medicine
Los Angeles, CA 90024
kerik@ucla.edu
References
Suntharalingam G, Perry MR, Ward S, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 2006;355:1018-1028.
To the Editor: We believe that the cytokine-release syndrome strongly resembles the toxic shock syndrome, which is induced by a staphylococcal superantigen that activates T cells, through their antigen receptor, to induce massive cytokine release.1 However, mice with deletion of the CD28 gene are protected from superantigen-induced, toxic shock syndrome–like disease.2 In addition, peptides that block binding to CD28 also block superantigen-dependent cytokine secretion by T cells.3 Together, these observations indicate that T cells activated by superantigen binding to both CD28 and the antigen receptor mediate the toxic shock syndrome.
CD28-deficient mice are protected from lethal superantigen challenge through the selective abrogation of the release of tumor necrosis factor (TNF).2 Because TNF is also strongly induced by anti-CD28 antibodies and TNF infusion can induce toxic shock syndrome–like disease,4 short-term use of anti-TNF agents may benefit patients with the toxic shock syndrome and related syndromes involving "cytokine storm."
David B. Corry, M.D.
Dorothy E. Lewis, Ph.D.
Baylor College of Medicine
Houston, TX 77030
dcorry@bcm.tmc.edu
References
McCormick JK, Yarwood JM, Schlievert PM. Toxic shock syndrome and bacterial superantigens: an update. Annu Rev Microbiol 2001;55:77-104.
Saha B, Harlan DM, Lee KP, June CH, Abe R. Protection against lethal toxic shock by targeted disruption of the CD28 gene. J Exp Med 1996;183:2675-2680.
Arad G, Levy R, Hillman D, Kaempfer R. Superantigen antagonist protects against lethal shock and defines a new domain for T-cell activation. Nat Med 2000;6:414-421.
Remick DG, Kunkel RG, Larrick JW, Kunkel SL. Acute in vivo effects of human recombinant tumor necrosis factor. Lab Invest 1987;56:583-590.
To the Editor: CD28 expression by human neutrophils has been documented, and its activation alone results in the secretion of interferon-.1 We now find that a subgroup of human neutrophils expresses the T-cell receptor (Figure 1). We have also shown that costimulation of the T-cell receptor and CD28 triggers the release of interleukin-8 in these cells.2 Therefore, neutrophils may represent a quantitatively important target of TGN1412 and may link the pathogenesis of the cytokine-release syndrome to the innate immune system.
Figure 1. Human Neutrophils Expressing the T-Cell Receptor.
Expression of the T-cell receptors and (indicated in red) is shown in a normal human peripheral-blood neutrophil (Panel A) and in a lymphocyte from the same person, used as a control cell (Panel B). Cells were double-stained with a monoclonal antibody against the T-cell receptors and (red) and the neutrophil marker CD15 (green); the nuclei were counterstained with 4',6-diamidine-2-phenylidole dihydrochloride (blue). Panel C shows the presence of the T-cell receptors and on the surface of a peripheral-blood neutrophil on immunogold electron microscopy. Arrows indicate T-cell receptor heterodimers (pairs).
Kerstin Puellmann, M.D.
Alexander W. Beham, M.D.
University of Regensburg
93053 Regensburg, Germany
kerstin.puellmann@web.de
Wolfgang E. Kaminski, M.D.
University of Heidelberg
68167 Mannheim, Germany
References
Venuprasad K, Banerjee PP, Chattopadhyay S, et al. Human neutrophil-expressed CD28 interacts with macrophage B7 to induce phosphatidylinositol 3-kinase-dependent IFN-gamma secretion and restriction of Leishmania growth. J Immunol 2002;169:920-928.
Puellmann K, Kaminski WE, Vogel M, et al. A variable immunoreceptor in a subpopulation of human neutrophils. Proc Natl Acad Sci U S A 2006;103:14441-14446.
To the Editor: The TGN1412-exposed patients described by Suntharalingam et al. had many of the clinical and laboratory features of the macrophage activation syndrome, also known as secondary hemophagocytic lymphohistiocytosis, a severe and sometimes fatal condition.1,2 Unfortunately, important diagnostic criteria for the macrophage activation syndrome,3,4 such as increased ferritin and soluble CD25 levels, enhanced activity of natural killer cells, and specific histologic characteristics of bone marrow, were not reported in these patients. Also, hepatosplenomegaly and lymphadenopathy, which are classic features of the macrophage activation syndrome, were absent in the volunteers exposed to TGN1412, perhaps because of the very acute nature of the reaction. If characterized further, TGN1412 may provide insight into the mechanisms that lead to the macrophage activation syndrome in other clinical settings, such as juvenile idiopathic arthritis or sepsis. This understanding may also help in the handling of future situations similar to the one described by Suntharalingam et al., in which evidence from clinical trials, including those involving patients with the macrophage activation syndrome, could help guide the care of the affected patients.3
Facundo Garcia-Bournissen, M.D.
Mariana Boragina, M.D.
Shinya Ito, M.D.
Hospital for Sick Children
Toronto, ON M5G 1X8, Canada
facundo.garciabournissen@sickkids.ca
References
Emmenegger U, Schaer DJ, Larroche C, Neftel KA. Haemophagocytic syndromes in adults: current concepts and challenges ahead. Swiss Med Wkly 2005;135:299-314.
Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child 2001;85:421-426.
Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer (in press).
Ravelli A, Magni-Manzoni S, Pistorio A, et al. Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr 2005;146:598-604.
To the Editor: Suntharalingam et al. report severe adverse events in the phase 1 study of TGN1412. Monoclonal antibodies, which cannot be metabolized in the liver and cannot be eliminated from the kidney, usually have long half-lives.1 Double filtration plasmapheresis, which selectively removes high-molecular-weight substances, including immunoglobulins and immune complexes, has been proven to be effective for the clearance of circulating monoclonal antibodies,2 and some studies have shown the usefulness of continuous hemofiltration or continuous hemodiafiltration for ameliorating cytokine storm.3,4 We would like the authors to comment on whether these therapeutic measures might be beneficial for the treatment of severe adverse events associated with monoclonal antibodies.
Morihito Takita, M.D.
Tomoko Matsumura, M.D.
Masahiro Kami, M.D.
University of Tokyo
Tokyo 108-8639, Japan
References
Expert scientific group on phase 1 clinical trials: interim report. London: Secretary of State for Health, July 2006. (Accessed November 22, 2006, at http://www.dh.gov.uk/assetRoot/04/13/75/69/04137569.pdf.)
Yeh JH, Chen WH, Chiu HC, Bai CH. Clearance studies during subsequent sessions of double filtration plasmapheresis. Artif Organs 2006;30:111-114.
Heering P, Morgera S, Schmitz FJ, et al. Cytokine removal and cardiovascular hemodynamics in septic patients with continuous venovenous hemofiltration. Intensive Care Med 1997;23:288-296.
Iglesias J, Marik PE, Levine JS. Elevated serum levels of the type I and type II receptors for tumor necrosis factor-alpha as predictive factors for ARF in patients with septic shock. Am J Kidney Dis 2003;41:62-75.
The authors reply: The psychological effect of serious adverse events on healthy subjects involved in clinical trials is important; critical illness has its own known neuropsychological consequences.1,2 Our institution does provide follow-up after discharge of patients who stay in the intensive care unit for more than 3 days. However, our article was limited to the physiological and immunologic events that occurred within 30 days after exposure; the omission cited by Gardner does not make the report incomplete.
Corry and Lewis suggest that the cytokine storm induced by TGN1412 is similar to that resulting in the toxic shock syndrome, on the basis of the activation of CD28 on T cells. Although T cells were the intended targets of TGN1412, it is still unclear whether T-cell activation induced the cytokine storm. The trigger may have been on another type of cell expressing CD28, as suggested by Puellmann et al., or may have involved ligation of Fc receptors. Hence the macrophage activation syndrome was also considered. Since the neutrophil count was preserved and, as noted by Garcia-Bournissen et al., there was neither hepatosplenomegaly nor lymphadenopathy, we thought that the macrophage activation syndrome as a separate entity should be ruled out. Our article was a clinical report of the unintended consequences of a phase 1 trial and subsequent emergency care. Laboratory investigations were limited to those that were of direct clinical benefit.
Anti-TNF therapy was considered. When transfer to our care took place 12 to 16 hours after TGN1412 infusion, we decided that the TNF peak was likely to have passed and that downstream events had already been triggered. As cytokine data became available, showing persistently high TNF levels, this decision was reviewed. In our minds, in the setting of severe lymphopenia and monocytopenia of unknown duration, treatment with high-dose corticosteroids and anti–interleukin-2 receptor antagonist antibody, and the increased risk of secondary infections in the patients, the risk of anti-TNF therapy still outweighed its potential benefit. We would be yet more cautious with a cause associated with infection, such as the toxic shock syndrome.
We agree with Takita et al. Plasmapheresis was considered, but the known pharmacokinetics of a low IgG4 antibody level suggested that the drug would be tissue-bound. We also agree that there may be a role for continuous venovenous hemodiafiltration in blunting the cytokine storm associated with a severe systemic inflammatory response. Furthermore, high dialysate rates3 and high-cutoff filters4 have previously been suggested for use in treating sepsis. Our patients received continuous venovenous hemodiafiltration at an initial dialysate rate of 1 liter per hour, which was subsequently raised to 4 liters per hour, using standard membranes. In our opinion, aggressive multiorgan support and early institution of high-volume diafiltration and treatment with high-dose corticosteroids, combined with the physiological resilience of these six young, healthy research volunteers, were key to their survival.
Andrew Castello-Cortes, F.R.C.A.
Ganesh Suntharalingam, F.R.C.A.
Northwick Park and St. Mark's Hospital
London HA1 3UJ, United Kingdom
ganesh.suntharalingam@nwlh.nhs.uk
Nicki Panoskaltsis, M.D., Ph.D.
Imperial College London
London HA1 3UJ, United Kingdom
References
Sukantarat KT, Burgess PW, Williamson RC, Brett SJ. Prolonged cognitive dysfunction in survivors of critical illness. Anaesthesia 2005;60:847-853.
Jackson JC, Hart RP, Gordon SM, et al. Six-month neuropsychological outcome of medical intensive care unit patients. Crit Care Med 2003;31:1226-1234.
Cole L, Bellomo R, Journois D, Davenport P, Baldwin I, Tipping P. High-volume haemofiltration in human septic shock. Intensive Care Med 2001;27:978-986.
Morgera S, Klonower D, Rocktaschel J, et al. TNF-alpha elimination with high cut-off haemofilters: a feasible clinical modality for septic patients? Nephrol Dial Transplant 2003;18:1361-1369.